Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Using the rat superior cervical ganglion in vitro, the relative efficacy of nicotinic synaptic transmission was estimated by recording the postganglionic compound action potential and the amount of endogenous acetylcholine (ACh) released. These two parameters were correlated in individual ganglia by sampling the bathing medium for the assay of ACh while simultaneously recording the postganglionic response. 2. The beta-adrenoceptor agonist isoprenaline potentiated both the evoked release of ACh and the postganglionic response by about 20% during preganglionic stimulation at 0.2 Hz. 3. The adenosine receptor agonist 2-chloroadenosine inhibited ACh release and the postganglionic response by about 35%. 4. Tetanic preganglionic stimulation for a few seconds induced a long-term potentiation of nicotinic responses and of ACh release. Both of these potentiations were dependent upon extracellular Ca2+ during the tetani. 5. Forskolin and analogues of cyclic AMP also caused a long-lasting potentiation of both the evoked release of ACh and the postganglionic response, indicating that cyclic AMP may regulate transmission by a presynaptic mechanism. The specificity of the cyclic AMP analogues was tested using various butyryl- and bromo-purine nucleotides. 6. The effects of forskolin and 8-bromo-cyclic AMP did not appear to be dependent upon extracellular Ca2+. 7. The potentiation caused by forskolin was consistently augmented by three phosphodiesterase inhibitors--AH 21-132, papaverine and SQ 20-006. However, the effect of forskolin was not consistently enhanced by theophylline, nor was it reduced by the adenylate cyclase inhibitor SQ 22-536. 8. The neurogenic long-term potentiation was augmented by two of the phosphodiesterase inhibitors that also augmented the forskolin-induced potentiation--papaverine and SQ 20-006. 9. It was concluded that cyclic AMP can enhance nicotinic transmission, and can do so by increasing the evoked release of ACh. However, it was not possible to prove that cyclic AMP mediates the long-term potentiation induced by tetanic preganglionic stimulation.
...
PMID:Long-term regulation of synaptic acetylcholine release and nicotinic transmission: the role of cyclic AMP. 283 71

Changes in cyclic AMP concentrations were studied in intact PC12 pheochromocytoma cells exposed to a variety of treatments. A marked increase was triggered by N-(L-2-phenylisopropyl)adenosine, the activator of an adenosine receptor, whereas a decrease (observed even after phosphodiesterase blockade) was induced by carbachol, working through a muscarinic receptor inhibited by the selective muscarinic blocker pirenzepine, only at high concentration (Ki 450 nM). A decrease in cyclic AMP was also induced by clonidine, an alpha 2-adrenergic-receptor agonist. Both the alpha 2-adrenergic and the muscarinic inhibitions were prevented by pretreatment of the cells with pertussis toxin, and were unaffected by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate. The latter drug caused a decrease in the resting cyclic AMP concentrations, and a potentiation of the increase induced by adenosine-receptor activation. Except for clonidine, all these treatments were found to be effective in both growing PC12 cells and, although to a smaller degree, in cells that had stopped growing and had acquired a neuron-like phenotype after prolonged treatment with nerve growth factor (NGF). Neither forskolin (a direct activator of adenylate cyclase) nor the activation of adenosine and alpha-adrenergic receptors was able to modify the resting cytosolic Ca2+ concentration [Ca2+]i in PC12 cells. Likewise, the K+-induced [Ca2+]i transients were unchanged after these treatments, whereas the transients induced by carbachol through the activation of a muscarinic receptor highly sensitive to pirenzepine were moderately potentiated by forskolin (and, to a lesser degree, by the adenosine analogue) and attenuated by clonidine. These results characterize in further detail the spectrum and the mutual interrelationships of the intracellular signals induced by receptor activation in PC12 cells, also as a function of the NGF-induced differentiation.
...
PMID:Second-messenger generation in PC12 cells. Interactions between cyclic AMP and Ca2+ signals. 285 Jul 95

In the present experiments we have examined the effect of N-ethylmaleimide (NEM) on the release of [3H]glutamate from rat hippocampal slices. Pretreatment of slices with NEM in a concentration between 50 microM and 200 microM, can inhibit the GTP-binding protein (Ni) that transmits receptor signals into inhibitions of adenylate cyclase, without affecting the Ns-protein, that transmits signals into stimulation of the cyclase, or the cyclase. The adenosine receptor agonist R-phenylisopropyladenosine (R-PIA, 1 microM) caused an approximately 50% inhibition of the evoked [3H]glutamate release. This effect was completely prevented by NEM treatment, which did not affect basal or stimulated release of the amino acid. By contrast, the effect of R-PIA was unaffected by adding an adenylate cyclase stimulator (forskolin 1 microM) and a phosphodiesterase inhibitor (rolipram, ZK 62.711, 30 microM) which raised the cyclic AMP content of the slices approximately 10-fold. In conclusion, these results suggest that the adenosine receptor that mediates prejunctional inhibition of glutamate release is coupled to a protein similar to the Ni-protein, but that another effector than adenylate cyclase is involved.
...
PMID:Effects of N-ethylmaleimide and forskolin on glutamate release from rat hippocampal slices. Evidence that prejunctional adenosine receptors are linked to N-proteins, but not to adenylate cyclase. 287

CGS 15943A, a triazoloquinazoline, is a potent and selective adenosine receptor antagonist as assessed by its effects on radioligand binding and adenosine-stimulated adenylate cyclase activity in guinea pig synaptoneurosomes. At the adenosine A-1 receptor labeled with [3H]cyclohexyladenosine, CGS 15943A had an IC50 value of 20 nM. At the striatal A-2 receptor labeled with [3H]5'-N-ethylcarboxamidoadenosine in the presence of a low concentration of cyclopentyladenosine to block A-1 receptors labeled by this nonselective adenosine agonist, CGS 15943A had an IC50 value of 3 nM, indicating that the compound had some degree of selectivity for the A-2 receptor. Analysis of the effect of the compound on the saturation isotherms for each of the receptors indicated that it was a competitive antagonist at the brain A-1 receptor but that it was noncompetitive at the striatal A-2 receptor. CGS 15943A was a potent adenosine antagonist in the adenosine-stimulated adenylate cyclase system in guinea pig synaptoneurosomes, where the compound was found to have an IC50 value of 30 to 70 nM against the increase in cyclic AMP evoked by 5 microM adenosine. CGS 15943A had no effect on the binding of [3H]nitrobenzylthioinosine, a ligand thought to bind to adenosine uptake sites, and, at a concentration of 10 microM, had no effect on beef heart type III phosphodiesterase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Biochemical characterization of the triazoloquinazoline, CGS 15943, a novel, non-xanthine adenosine antagonist. 288 98

Previous studies showed that acute treatment with aminophylline (AMPY) significantly elevated maximum thermogenesis and improved cold tolerance in rats and man in severe cold. However, the exact mechanism by which AMPY enhances thermogenesis was unknown. Rats receiving enprofylline (ENPRO) (1.5 and 15 mg/kg, i.p.), a selective phosphodiesterase inhibitor, failed to show enhanced thermogenesis. In contrast, treatment with a selective adenosine receptor antagonist, 8-phenyltheophylline(8-PT; 2.5 to 10 mg/kg, i.p.), significantly increased (p less than 0.05) thermogenesis and cold tolerance. However, the maximal thermogenic effect by optimal dose of 8-PT (5 mg/kg) was significantly lower than that with optimal dose of AMPY (18.7 mg/kg, i.p.); the deficit could be eradicated by combining optimal 8-PT dose with a low dose of AMPY (1.25 mg/kg), but not with ENPRO. These results indicate that the thermogenic effect of AMPY is not by inhibition of phosphodiesterase but at least partially by antagonism of adenosine receptors. It is also apparent that older mechanisms in addition to adenosine antagonism are also involved in AMPY's thermogenic action.
...
PMID:Mechanisms underlying the supra-maximal thermogenesis elicited by aminophylline in rats. 292 50

The interaction of ADP with platelets leads to shape change, exposure of fibrinogen binding sites, and aggregation, all of which have been shown to be inhibited by 5'-p-fluorosulfonylbenzoyladenosine (FSBA), an alkylating analogue of adenine nucleotides which binds covalently to a 100-kDa polypeptide in intact platelet membranes (Figures, W. R., Niewiarowski, S., Morinelli, T., Colman, R. F., and Colman, R. W. (1981) J. Biol. Chem. 256, 7789-7795). In plasma, FSBA can break down to adenosine which stimulates adenylate cyclase. To distinguish between direct effects of FSBA and the actions of adenosine, we have used washed platelet suspensions and adenosine deaminase. We studied the effects of FSBA on shape change and cyclic AMP metabolism, and on the binding of 2-methylthio-ADP, which mimics the effects of ADP on cyclic AMP metabolism at concentrations too low to activate platelets. Inhibition of ADP-induced shape change of platelets incubated with FSBA for 2 min in platelet-rich plasma was greatly reduced by adenosine deaminase. In the presence of a phosphodiesterase inhibitor, 100 microM FSBA increased platelet cyclic AMP to the same extent as did 10 microM adenosine. These effects were inhibited by theophylline, an adenosine receptor antagonist, and by adenosine deaminase. Incubation of washed platelets for 60 min with FSBA and adenosine deaminase caused a concentration-dependent inhibition of ADP-induced shape change. Inhibition closely paralleled the covalent incorporation of 3H from tritiated FSBA into platelet membranes. Under these conditions, FSBA did not block inhibition of cyclic AMP accumulation by ADP, nor did it block the binding of 2-methylthio-ADP. We conclude that part of the inhibition of shape change caused by brief exposure to FSBA is due to adenosine, but at longer times shape change is inhibited in association with covalent incorporation of sulfonylbenzoyladenosine. This effect of FSBA is independent of adenosine and occurs at a site distinct from that at which ADP inhibits adenylate cyclase.
...
PMID:Two mechanisms for inhibition of ADP-induced platelet shape change by 5'-p-fluorosulfonylbenzoyladenosine. Conversion to adenosine, and covalent modification at an ADP binding site distinct from that which inhibits adenylate cyclase. 298 76

This study was designed to examine: (a) the effects of adenosine and its analogues on renin release in the absence of tubules, glomeruli, and macula densa, and (b) whether adenosine may be involved in a macula densa-mediated renin release mechanism. Rabbit afferent arterioles (Af) alone and afferent arterioles with macula densa attached (Af + MD) were microdissected and incubated for two consecutive 30-min periods. Hourly renin release rate from a single arteriole (or an arteriole with macula densa) was calculated and expressed as ng AI X h-1 X Af-1 (or Af + MD-1)/h (where AI is angiotensin I). Basal renin release rate from Af was 0.69 +/- 0.09 ng AI X h-1 X Af-1/h (means +/- SEM, n = 16) and remained stable for 60 min. Basal renin release rate from Af + MD was 0.20 +/- 0.04 ng AI X h-1 X Af + MD-1/h (n = 6), which was significantly lower (P less than 0.0025) than that from Af. When adenosine (0.1 microM) was added to Af, renin release decreased from 0.72 +/- 0.16 to 0.24 +/- 0.04 ng AI X h-1 X Af-1/h (P less than 0.025; n = 9). However, when adenosine was added to Af + MD, no significant change in renin release was observed. N6-cyclohexyl adenosine (an A1 adenosine receptor agonist) at 0.1 microM decreased renin release from Af from 0.69 +/- 0.14 to 0.39 +/- 0.12 ng AI X h-1 X Af-1/h (n = 5, P less than 0.05). However, 5'-N-ethylcarboxamide adenosine (an A2 adenosine receptor agonist) either at 0.1 microM or at 10 microM had no effect. Theophylline, at a concentration (10 microM) that does not block phosphodiesterase but does block adenosine receptors, increased renin release from Af + MD from 0.21 +/- 0.03 to 0.46 +/- 0.08 ng AI X h-1 X Af + MD-1/h (P less than 0.05; n = 8). The results are consistent with the hypotheses that adenosine decreases renin release via the activation of A1 adenosine receptors, and that adenosine may be an inhibitory signal from the macula densa to juxtaglomerular cells.
...
PMID:Possible role of adenosine in the macula densa mechanism of renin release in rabbits. 299 77

Three major classes of Ca2+ entry blockers, classified according to effects on cardiac and vascular smooth muscle, were tested. Vesicles prepared from cerebral cortex and stimulated by adenosine and epinephrine constituted adenosine and alpha-adrenergic receptor systems respectively. Vesicles prepared from cerebellum and stimulated by epinephrine constituted the beta-adrenergic receptor system. Experiments with adenosine were also performed with vesicles formed or incubated in the absence of exogenous Ca2+. The results indicate that Ca2+ entry blockers had a variety of effects, even within classes of drugs. Vascular-selective group A Ca2+ entry blockers such as nifedipine and nisoldipine antagonized adenosine, but the structurally-related drug nitrendipine was inactive. Inhibition was competitive with adenosine and independent of exogenous Ca2+. In contrast to receptor-binding studies requiring high ratios of the drugs to adenosine receptor radioligands, nifedipine and nisoldipine were inhibitory at equimolar concentrations with adenosine. Non-selective group A Ca2+ entry blockers such as diltiazem and verapamil were inactive against adenosine. Group B Ca2+ entry blockers, prenylamine and perhexilene, increased cyclic AMP (cAMP) levels of vesicles stimulated by adenosine but not by epinephrine or under basal conditions. This effect was observed only in vesicles that had been formed in the presence of Ca2+. Ca2+ entry blockers also exhibited effects on adrenergic receptors unrelated to effects on adenosine. Verapamil and prenylamine acted as alpha-adrenergic antagonists and only prenylamine acted as a beta-adrenergic antagonist. However, the vesicle system also revealed indirect blocking actions of nifedipine on adrenergic receptor systems. The actions of the Ca2+ entry blockers are discussed in relation to the special usefulness of nifedipine in the treatment of patients with defective atrioventricular conduction and also in relation to the unique ability of group B Ca2+ entry blockers to selectively inhibit Ca2+ and calmodulin activated phosphodiesterase. However, some caution must be applied in drawing conclusions relating to the cardiovascular actions of these drugs from data generated in a neuronally-derived model.
...
PMID:Differences in Ca2+ entry blockers revealed by effects on adenosine- and adrenergic- receptors and cyclic AMP levels of [2-3H]adenine-prelabeled vesicles prepared from guinea pig brain. 301 Oct 9

Methylxanthines have been used for the treatment of asthma for more than 60 years, but their mechanism of action is poorly understood. Their ability to inhibit cyclic adenosine monophosphate phosphodiesterase has attracted much attention. However, this is clearly demonstrable only in high doses and is more likely to be related to toxicity. An alternative mechanism is antagonism of adenosine receptors in the lung. Adenosine has been shown to be released in asthma and cause bronchoconstriction in patients with asthma. Its effects are selectively inhibited by concentrations of theophylline that do not block histamine-induced bronchoconstriction. Neither phosphodiesterase inhibition nor adenosine receptor antagonism explains the action of enprofylline in asthma. Consequently, additional actions of methylxanthines are likely to contribute to their beneficial effects. They may include adrenaline release from the adrenal medulla, an effect on cell calcium distribution, inhibition of the generation of contractile prostaglandins, and an improvement of diaphragmatic contractility.
...
PMID:Relationships between adenosine, cyclic nucleotides, and xanthines in asthma. 302 33

The intact rat adipocyte was used to investigate the possibility of common intermediates in the insulin stimulation of cyclic AMP phosphodiesterase and the beta-adrenergic/adenosine regulation of adenylate cyclase. A five minute incubation of the isolated adipocytes with insulin produced a 50-100% increase in the phosphodiesterase activity found in the particulate fraction of homogenates. The insulin stimulation was not impaired by the presence of either agonist or antagonists of the inhibitory adenosine receptor which acts on adenylate cyclase. Phosphodiesterase activation by insulin was also observable above the level of stimulation produced by the beta-adrenergic agent isoproterenol and forskolin. The validity of the enzyme activity measurements was supported by measurements of the hormonal actions on cyclic AMP levels within the cells. Possible crossover between the adenylate cyclase and phosphodiesterase regulation systems at a post-receptor site was investigated using adipocytes exposed to bacterial toxins specific for the modification of guanine nucleotide binding proteins. Both cholera toxin, which irreversibly activates Gs and pertussis toxin which inactivates Gi caused some stimulation of the phosphodiesterase activity and suppressed activation by isoproterenol, but neither toxin prevented the insulin stimulation of cyclic AMP phosphodiesterase. These results suggest, while common components may participate in the beta-adrenergic stimulation of both adenylate cyclase and phosphodiesterase, the mechanism of insulin activation of the phosphodiesterase does not involve the components of adenylate cyclase regulation.
...
PMID:Insulin stimulation of cyclic AMP phosphodiesterase is independent from the G-protein pathways involved in adenylate cyclase regulation. 304 Aug 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---